We are examining the genetic load of natural populations from a biochemical standpoint. Computer simulations and studies of Drosophila isoenzymes have led us to the conclusion that the majority of polymorphic variability now present in natural populations consists of functional isoalleles with small but strongly environment- and genotype- dependent selection coefficients. We are using both in vitro enzyme assays and relative survival of various Drosophila esterase and octanol dehydrogenase genotypes to determine the conditions under which these selection coefficients can be enhanced and what sort of balancng selection maintains these polymorphisms in natural populations. Methods have been developed in our laboratory for the deliberate selection of functional isoallelic forms of yeast alcohol dehydrogenase. They have been selected to distinguish between allyl alcohol and ethanol as substrates, which the wildtype enzyme cannot do. We will use these enzymes to study conditional overdominance, partial dominance and the nature and relative frequency of adaptive mutations in greater detail than would be possible in a less well-defind system. We hope that this work will cast some light on the mechanism of adaptation of multimeric enzymes to changing environmental conditions, and eventually on the mechanism of action of ADH itself.